Project Summary/Abstract: Over the previous funding period, it was shown that the sulfur-containing amino acid methionine is a key signal of amino acid sufficiency. Methionine functions by boosting the synthesis of its downstream metabolite S-adenosylmethionine, which serves as the biological methyl donor in many one-carbon transfer reactions critical for life. This application proposes to comprehensively investigate the mechanisms by which methionine and SAM function to regulate important cellular pathways in balancing cell growth versus survival in response to metabolic state. A combination of genetics and biochemistry will be utilized to elucidate how methionine and SAM regulate phosphorylation-based signaling, epigenetic methylation modifications on chromatin, as well as the transcription and translation of sulfur metabolism genes. Insights from these studies will be informative as to the role of these sentinel metabolites in aging and age-related diseases.